Plasmodium infections, which cause malaria, have been a scourge to humanity for thousands of years. Unfortunately, we are still years away from an efficacious anti-malaria vaccine that is available to the >40% of the world's population that is at risk of malaria. Further complicating treatment and control of malaria is that both Plasmodium and the mosquito vector that transmits the parasite rapidly develop resistance to new drugs developed to treat malaria and control mosquito populations. Therefore, it is imperative novel approaches to control malaria are explored. We propose an exploratory project to determine the impact of the gut microbiota on regulating the severity of malaria, which has the potential to provide insights to novel and affordable approaches to treat malaria. The gut microbiota has been shown to shape susceptibility to obesity, diabetes, and regulate multiple aspects of host immunity. This is particularly true for components of the immune system that interface with the GI tract. Importantly, the gut microbiota also augments host immunity to bacterial and viral infections that occur outside of the GI tract. However, there are no reports as to how the gut microbiota influence host immune responses to non-GI tract parasitic infections, including Plasmodium. Our preliminary data demonstrate that C57BL/6 mice purchased from different vendors, which are known to have alterations in their gut microbiota, exhibit substantially different levels of parasite burden following infection with Plasmodium yoelii 17XNL. We have also demonstrated that C57BL/6 mice from different vendors treated with a cocktail of antibiotics exhibit dynamic responses following infection with Plasmodium compared to control treated mice. Collectively, our data suggest the gut microbiota regulates the severity of malaria. We hypothesize that specific gut bacteria and their metabolic by-products regulate susceptibility to malaria. We will address this hypothesis through the following specific aims: 1) Identify differences in gut microbiota populations that are associated with differential susceptibility to malaria, 2) Determine ability of the gut microbiota to transfer resistance or susceptibility to malaria to another mouse and 3) Identify gut metabolites that drive differential susceptibility to malaria.